Hydroxymethylimidazodiazepines and their esters

ABSTRACT

The invention is concerned with hydroxymethyl-imidazodiazepines and their esters of general formula I. These compounds can be used as anxiolytic and/or anticonvulsant and/or muscle relaxant and/or sedative-hypnotic active substances.

The present invention is concerned with hydroxymethylimidazodiazepinesand their esters of the general formula

wherein A and the two carbon atoms denoted by α and β together signifyone of the residues

R¹ signifies hydrogen or lower-alkanoyl;

R² signifies phenyl, o-halophenyl or 2-pyridyl;

R³ signifies hydrogen, lower-alkyl, methylaminomethyl, allylaminomethylor diethylaminomethyl;

R⁴ signifies halogen, CF₃ or nitro;

R⁵ signifies hydrogen or halogen,

as well as pharmaceutical acceptable salts thereof.

These compounds and salts are novel and have valuable pharmacodynamicproperties. They are therefore suitable for therapeutic purposes,especially for anxiolytic and/or anticonvulsant and/or muscle relaxantand/or sedative-hypnotic purposes. A particular advantage of the novelcompounds of general formula I is the good water solubility of theirsalts as well as a short duration of action for the uses referred toabove.

Objects of the present invention are the mentioned compounds of formulaI and salts thereof per se and as therapeutically active substances,their manufacture and their use for therapeutic purposes and,respectively, for the production of corresponding medicaments as well asmedicaments containing a compound of formula I or a salt thereof and theproduction of such medicaments.

The term “lower” denotes residues or compounds with a maximum of 7,preferably a maximum of 4, carbon atoms. The term “alkyl” denotesstraight-chain or branched saturated hydrocarbon residues, such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, sec.-butyl, iso-butyl andtert.-butyl. The term “alkenyl” denotes straight-chain or branchedhydrocarbon residues which contain a C—C double bond, such as allyl,but-2-enyl, 3-methyl-but-2-enyl and the like. The term “halogen”embraces fluorine, chlorine, bromine and iodine. The term “amino”denotes residues such as NH₂, NH-lower-alkyl, N-di-loweralkyl,NH-lower-alkenyl, morpholino, piperidino, pyrrolidin-1-yl,methylpiperiazin-1-yl and the like. The term “alkanoyl” denotes residuessuch as acetyl, propionyl and the like.

When A in formula I signifies a residue of formula A¹, there arepreferred those compounds in which R¹ signifies hydrogen, R² signifieso-fluoro- or o-Cl-phenyl, R³ signifies hydrogen or allylaminomethyl andR⁴ iodine or chlorine.

The following compounds are examples of these:

8-Chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a]benzodiazepine-2methanol;

1-allylaminomethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol;

8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol;

8-iodo-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol.

When A in formula I signifies a residue of formula A², there arepreferred those compounds in which R¹ signifies hydrogen orcarbonylmethyl, R² signifies o-fluorophenyl, R³ signifies hydrogen andR⁵ signifies chlorine.

The following compounds are examples of these:

2-Chloro-4-(2-fluorophenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepine-8-methanol;

methyl[2-chloro-4-(2-fluorophenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f]diazepin-8-yl]acetate.

The compounds of general formula I mentioned earlier and theirpharmaceutically acceptable acid addition salts can be manufactured inaccordance with the invention by

a) converting compounds of the general formulae

with a basic reagent into compounds of the general formula

 wherein A, R² and R³ have the above significance, or

b) converting compounds of general formula Ia or IIa into compounds ofthe general formula

 wherein A, R² and R³ have the above significance and R⁶ signifieslower-alkanoyl, or

c) hydrolyzing compounds of general formula Ib to compounds of generalformula Ia, or

d) reducing compounds of the general formula

 wherein A, R² and R³ have the above significance and R⁵ signifieslower-alkyl, to compounds of the general formula

or

e) cleaving off the protecting group from a compound of the generalformula

 wherein A and R² and R³ have the above significance and R⁴ signifies aprotecting group, or

f) cyclizing compounds of the general formula

 wherein A and R² have the above significance and R⁵ signifieslower-alkyl, in an acidic medium to compounds of general formula I inwhich R³ signifies hydrogen, and

g) if desired, converting a compound of general formula I into apharmaceutically usable acid addition salt.

Compounds of general formula Ia can be manufactured according to processvariant a) by treating compounds of formulae IIa with a basic reagent.This is conveniently carried out as follows: a compound of formula IIais stirred under a protective gas atmosphere for several hours in analkali hydroxide solution, preferably in sodium hydroxide, or treatedwith sodium hydrogen carbonate and subsequently worked up according toknown methods.

Compounds of general formula Ib are obtained in accordance with processvariant b) starting from compounds of formula Ia by reacting thesecompounds conveniently with acetic anhydride or the like in the presenceof strong acid, for example perchloric acid, or starting from a compoundof formula IIa by reacting this with sodium acetate or the like. Thesemethods will be familiar to any person skilled in the art.

The compounds of general formula Ib are hydrolyzed to compounds ofgeneral formula Ia according to process variant c). This is convenientlyeffected with a methanolic sodium methanolate solution.

Compounds of formula Ia are obtained in accordance with process variantd). This is effected by reducing a compound of general formula III witha suitable reducing agent, for example with a lithium aluminum hydridesolution. This is conveniently carried out as follows: the reducingagent is dissolved in a suitable organic solvent, for exampletetrahydrofuran, cooled to about −70 to −80° C. and treated with asolution of a compound of general formula III. After a reaction periodof about 1 hour the mixture is warmed slowly to 0° C. and subsequentlyworked up according to usual methods.

Compounds of general formula la are obtained in accordance with processvariant e). Suitable protecting groups and methods for their cleavagewill be familiar to any person skilled in the art, although, of course,only those protecting groups can be used which can be cleaved off bymethods under the conditions of which other structural elements in thecompounds are not concomitantly effected. Compounds of general formula Iin which R¹ signifies hydrogen and R³ signifies aminomethyl and R² hasthe significance set forth above can be conveniently manufactured byconverting a compound of general formula IVb which carries a protectinggroup into compounds of general formula Ia in one process step bytreating the reactive compounds of formula IVb with a correspondingamine and by simultaneously cleaving off the protecting group by workingin the acidic range. The following are especially preferred amines:diethylamine, morpholine, methylamine, allylamine and the like.

The compounds of formula I are converted into pharmaceuticallyacceptable acid addition salts in accordance with process variant g).Salts with both inorganic acids and organic acids come intoconsideration. Examples of such salts are the hydrochlorides,hydrobromides, sulphates, nitrates, citrates, acetates, maleates,succinates, methanesulphonates, p-toluenesulphonates and the like. Thesesalts can be manufactured according to methods which are known per seand which will be familiar to any person skilled in the art.

The starting products of formulae Ia, III, IVb and V above can beprepared in accordance with Scheme 1 or 2 hereinafter.

In Schemes 1 and 2 A and R² have the significance set forth above, R⁵signifies lower-alkyl and R⁶ signifies halogen.

The compounds of general formulae IX and XIV have a central significancefor the manufacture of the compounds of general formula I in accordancewith the invention. They can be prepared in accordance with Scheme 1 bydifferent routes. These possibilities are described in detail inExamples 1a, 1b, 1c, 3a, 3b, 4, 14a, 14b, 15a, 16a, 17a, 18a, 19a, 19b,20a, 20b, 20c and 20d. The compounds of general formulae IX and XIV areknown compounds and are described in J. Med. Chem., 1971, 14, 1978-1081;Am. Chem. Soc., 1953, 75, 6244; Yakugaku Zasshi, 1973, 93, 1253-1262; J.Chem. Res. Synop., 1980, 400; J. Med. Chem., 1991, 34, 1209; J. Med.Chem., 1980, 23, 392-402; DE-OS 2 233 483.

The preparation of a compounds of formula IIIa starting from a compoundof general formula IX will be described in more detail on the basis ofan example in which A and R² have the above significance and Alksignifies ethyl.

A corresponding diazepine of general formula IX is treated in successionwith N-ethyldiisopropylamine and ethyl bromopyruvate (Ex. 18), dissolvedin tetrahydrofuran, while warming for several minutes, cooled, treatedwith diethyl ether and the resulting N-ethyldiisopropylaminehydrobromide is filtered off. The filtrate was subsequently convertedinto the target compounds of formula IIIa according to known methods.

Compounds of general formula IIa are obtained in accordance with Scheme1 by reacting a compound of general formula IX with 1,3-dichloroacetonein the presence of sodium bicarbonate. This reaction is convenientlyeffected in an inert solvent, such as e.g. dioxan under a protective gasatmosphere at room temperature.

Compounds of general formula IIb are obtained in an analogous manner. Acompound of general formula IX is reacted with 1,3-dichloroacetone inthe presence of anhydrous potassium carbonate or sodium hydrogencarbonate in dioxan and subsequently worked up according to knownmethods.

Compounds of general formula V are obtained starting from compounds ofgeneral formula XIV by reacting a diazepine of general formula XIV with3,3-diethoxy-1-hydroxy-2-propylamine, dissolved in an alcohol, forexample in butanol. This is conveniently effected within several hourswhile warming.

Also set forth in Scheme 1 is a process variant which leads over severalsteps to the preparation of compounds of general formula IIIb.

Compounds of general formula XV are obtained starting from a compound ofgeneral formula XIV by alkylation. Methyl iodide is a suitablealkylating agent; however, other alkylating agents are also possible.

This is conveniently carried out by boiling a compound of generalformula XIV in the presence of potassium carbonate and the alkylatingagent dissolved in a suitable solvent, e.g. acetone, at reflux whilestirring. After working up has been effected the compound of formula Vis converted with L-threonine alkyl ester hydrochloride, dissolved inpyridine, into compounds of formula XVI. This compound is obtained as adiastereomer mixture, which is converted without purification intocompounds of general formula XVII. For this purpose, this compound,dissolved in dichloromethane, is added dropwise to a solution which isprepared as follows: a solution consisting of trifluoroacetic anhydridein dichloromethane is added dropwise to a cooled solution of dimethylsulphoxide and dichloromethane and this mixture is subsequently treatedwith a compound of general formula XVI. The compounds of general formulaXVII obtained are subsequently cyclized to compounds of general formulaIIIb. This is conveniently carried out in dimethylformamide in thepresence of p-toluenesulphonic acid monohydrate while warming.

Scheme 2 shows the preparation of compounds of general formula IVbstarting from compounds of general formula IX. This is convenientlycarried out as follows: a compound of general formula IX is reacted inthe presence of dimethyl dihydroxyfumarate and triphenylphosphine,dissolved in tetrahydrofuran, with diethyl azodicarboxylate, dissolvedin tetrahydrofuran, while cooling. After working up the resultingcompound of general formula XVIII is conveniently dissolved intetrahydrofuran and treated with oxalyl chloride in the presence ofdimethylformamide. The thus-obtained acid chloride is converted into XIXby methanolysis. XIX is subsequently reduced to compounds of generalformula XX. This is conveniently carried out according to generallyknown methods. Lithium aluminium hydride in tetrahydrofuran isespecially well suited as the reducing agent. After reduction has beencarried out the OH group at which no further reaction should take placeis protected. Conveniently, for this purpose the corresponding diazepineof general formula XX is reacted with tert-butyldimethylsilyl chlorideat room temperature in the presence of imidazole, dissolved indimethylformamide. The resulting compound of general formula IVa cansubsequently be converted with suitable activating agents, for exampletetrabromomethane, and triphenylphosphine, into reactive compounds ofgeneral formula IVb for further reactions according to generally knowmethods.

A detailed description of the compounds prepared in Scheme 2 is given inExamples 6a, 6b, 6c, 6d, 6e, 7, 8 and 9.

As mentioned earlier, the compounds of formula I are novel. They havevaluable pharmacodynamic properties and have only a low toxicity. Theyhave as a common feature a pronounced affinity to the centralbenzodiazepine receptors and have pronounced anxiolytic, anticonvulsant,muscle relaxant and sedative-hypnotic properties on the basis of theiragonistic activity at these receptors. They form acid addition saltswhich have a very good solubility in water and are therefore primarilysuitable for the production of aqueous injection solutions.

The affinity of compounds of general formula I to the centralbenzodiazepine receptors was established in vitro according to themethods described in Nature 294, 763-765 (1981) and J. Neurochemistry37, 714-722 (1981). According to these methods the inhibition of thebinding of tritiated flumazenil to the specific benzodiazepine receptorsin the cortex of rats by the respective test substances is determined.The IC₅₀ (“50% inhibiting concentration”) denotes that concentration ofthe respective test substance which brings about a 50 percent inhibitionof the specific binding of tritiated flumazenil to the specificbenzodiazepine receptors in the cortex of rats.

The sedative/muscle relaxant properties of the compounds of formula IIin accordance with the invention can be determined, for example, in therotating rod test. Mice weighing 19-21 g are used for this test. Theyhave free access to feed and drinking water up to 1 hour prior to thebeginning of the test. They are brought into the test laboratory atleast 30 minutes prior to the test. In the rotating rod test the animalsare placed on a horizontally arranged, smooth metal rod having adiameter of 3 cm., which is rotated at 2 revolutions per minute.Initially, the animals are given the opportunity of familiarizingthemselves with the test situation for 30 seconds. Subsequently, thoseanimals which succeed in remaining on the rod for at least 1 minute areselected. The test preparations are then administered intraveneously tothese animals in different dosages. At various points in time it is thendetermined whether the animals are able to remain for a minimum periodon the rod (minimum period: 10 seconds, 1 minute from 5 minutes afteradministration). That dosage at which 50% of the animals are capable ofremaining on the rod is determined (ED₅₀).

The results which have been obtained with representative members of theclass of compound defined by general formula I in the tests describedpreviously are compiled in the following Table.

TABLE Affinity to benzo- Rotating rod, test, ED₅₀ in mg/kg; i.v.,determed at the following points in Com- diazepine- time afterAdministration pound receptors Mimimun time:10 Minimum time:60 secExample IC₅₀[nmol] 15 sec. 30 sec. 60 sec. 2 min 5 min 15 min 30 min 60min A 2.6 0.5 0,7 0.6 1.2 2.3 5.3 ≧10 >10 1f, 2 B 6.0 0.6 0,7 1.2 1.0≧10 ≧10 ≧10 >10 1g C 1.7 0.1 0,3 0.3 ≧10 0.8 0.4 1.1 ≧10 4b, 10b D 5.62.5 3,0 3.2 3.2 2.1 1.8 ≧10 >10 9 E 1.2 ≦0.32 0,4 0.5 3.2 0.9 0.5 ≧3.2≧3.2 11 F 12.0 1.0 1,1 1.1 >3.2 1.0 0.9 1.1 1.8 13 G 2.3 0.2 0,2 0.3 0.30.1 0.2 0.2 ≧1 14c H 2.07 0.1 0.06 0.09 0.1 0.1 0.1 ≧1 >1 17b I 40 1.52.0  3.0 >10 1.4 1.8 3.0 ≧10 18c

Significances in this are:

A2-Chloro-4-(2-fluorophenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepine-8-methanol

BMethyl[2-chloro-4-(2-fluorophenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f]diazepin-8-y]acetate

C 8-Chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a]benzodiazepine-2-methanol

D1-Allylaminomethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

E 8-Chloro-6-(2-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2methanol

F 8-Trifluoromethyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2methanol

G 6-(2-Fluorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2methanol

H 6-(2-Fluorophenyl)-8-iodo-4H-imidazo[1,2-a][1,4]benzodiazepine-2methanol

I 8-Bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2 methanol

From the above Table it will be evident that compounds A to I display asedative activity which sets in very rapidly and lasts only a relativelyshort time.

Having regard to their agonistic activity at the benzodiazepinereceptors the compounds of formula I can be used as sedatives/hypnotics,anticonvulsants, muscle relaxants and anxiolytics. They are suitable,for example, as rapid but short acting hypnotics for peroraladministration, especially—in the form of aqueous solutions of theiracid addition salts—as injectable short acting hypnotics forpremedication, sedation as well as narcosis induction and narcosismaintenance; preferred possibilities for use are thus premedicationprior to narcosis induction, basal sedation prior to diagnostic orsurgical intervention with or without local anaesthesia, long termsedation in intensive care, use as an induction agent for inhalationnarcosis or as a sleep-inducing component of combination narcosis(including total intravenous anaesthesia) etc.

The compounds of formula I and pharmaceutically acceptable acid additionsalts thereof can be used as medicaments, e.g. in the form ofpharmaceutical preparations. The pharmaceutical preparations can beadministered orally, e.g. in the form of tablets, coated tablets,drag{acute over (e)}es, hard and soft gelatine capsules, solutions,emulsions or suspensions. The administration can, however, also beeffected rectally, e.g. in the form of suppositories, or parenterally,e.g. in the form of injection solutions.

The compounds of formula I and pharmaceutically acceptable acid additionsalts thereof can be processed with pharmaceutically inert, inorganic ororganic carriers for the production of pharmaceutical preparations.Lactose, corn starch or derivatives thereof, talc, stearic acid or itssalts and the like can be used, for example, as such carriers fortablets, coated tablets, drag{acute over (e)}es and hard gelatinecapsules. Suitable carriers for soft gelatine capsules are, for example,vegetable oils, waxes, fats, semi-solid and liquid polyols and the like;depending on the nature of the active substance no carriers are,however, required in the case of soft gelatine capsules. Suitablecarriers for the production of solutions and syrups are, for example,water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants,such as alcohols, polyols, glycerol, vegetable oils and the like, can beused for aqueous injection solutions of water-soluble acid additionsalts of compound of formula I, but as a rule are not necessary.Suitable carriers for suppositories are, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can also contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

As mentioned earlier, medicaments containing a compound of formula I ora pharmaceutically acceptable acid addition salt thereof and atherapeutically inert excipient are also an object of the presentinvention, furthermore also a process for the production of suchmedicaments which is characterized by bringing one or more compounds offormula I or pharmaceutically acceptable acid addition salts thereofand, if desired, one or more other therapeutically valuable substancesinto a galenical administration form together with one [or] moretherapeutically inert carriers.

As mentioned earlier, the compounds of formula I and pharmaceuticallyacceptable acid addition salts thereof can be used in accordance withthe invention for therapeutic purposes, especially for anxiolytic and/oranticonvulsant and/or muscle relaxant and/or sedative-hypnotic purposes.The dosage can vary within wide limits and will, of course, be fitted tothe individual requirements in each particular case. In general, in thecase of intravenous administration a daily dosage of about 1 mg to 1000mg should be appropriate. Finally, as mentioned earlier, the use ofcompounds of formula I and of pharmaceutically usable acid additionsalts thereof for the production of medicaments, especially ofanxiolytic and/or anticonvulsant and/or muscle relaxing and/orsedative-hypnotic medicaments, is also an object of the invention.

The following Examples are intended to illustrate the present inventionin more detail, but do not limit its scope in any manner.

EXAMPLE 1 Manufacture of2-chloro-4-(2-fluoro-phenyl)-8.9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepine-8-methanol

a) A suspension of 100 g of dihydrogen-hexachloro-stannatebis(thiophen-2-ylamine), 50.7 g of 2-fluorobenzonitrile and 54.7 g ofaluminium. chloride (anhydrous) in 380 ml of 1,2-dichloroethane and 750ml of toluene was stirred at room temperature while gassing withnitrogen for 0.5 h. and treated cautiously with 380 ml of borontrichloride (1M in xylene). The reaction mixture was stirred at 65° C.for 1 h. and at 110° C. for 5 h. The solution was poured into 1300 ml ofammonia (16% in methanol), 1000 ml of dichloromethane and ice,subsequently filtered through Hyflo. The organic phase was washed withsaturated sodium chloride solution, dried with sodium sulphate, filteredand evaporated to dryness in a vacuum. The residue, 73 g of crude3-[(2-fluoro-phenyl)-imino-methyl]-thiophen-2-ylamine was used as thestarting product for the step described below without furtherpurification.

b) A solution of 73 g of3-[(2-fluoro-phenyl)-imino-methyl]-thiophen-2-ylamine and 48 g ofaminoacetonitrile hydrochloride in 1150 ml of methanol was stirred at75° C. under argon for 1 h. The reaction mixture was extracted withwater/dichloromethane. The dichloromethane extracts were dried oversodium sulphate, filtered and evaporated to dryness in a vacuum. Theresidue (70 g)[(2-amino-thiophen-3-yl)-(2-fluoro-phenyl)-methyleneamino]acetonitrilewas used as the starting product for the step described below.

c) A solution of 70 g of[(2-amino-thiophen-3-yl)-(2-fluoro-phenyl)-methyleneamino]acetonitrilein 980 ml of acetic acid was stirred at 65° C. under argon for 1.5 h.After cooling the solvent was removed in a vacuum, the residue wasdissolved in dichloromethane and neutralized with sodium bicarbonatesolution while cooling with ice and extracted. The dichloromethaneextracts were dried with sodium sulphate, filtered and evaporated todryness in a vacuum. After crystallization from dichloromethane therewere obtained 17.1 g of5-(2-fluoro-phenyl)-3H-thieno[2,3-e][1,4]diazepin-2-ylamine of m.p.219-220° C. (dec.).

d) 19 g of 5-(2-fluoro-phenyl)-3H-thieno[2,3-e][1,4]diazepin-2-ylaminewere dissolved in 730 ml of 5% methanol in dichloromethane, treatedwhile stirring well with 327 g of a 2.8% solution of chlorine gas in 5%methanol in dichloromethane and stirred at room temperature under argonfor 5 minutes. Thereafter, the reaction mixture was poured into 600 mlof 0.2N sodium hydroxide solution while cooling with ice and extracted.The dichloromethane extracts were dried with sodium sulphate, filteredand the solvent was evaporated in a vacuum. After two fold boiling ofthe residue in 5% methanol in dichloromethane and filtration there wereobtained 7.4 g of7-chloro-5-(2-fluoro-phenyl)-3H-thieno[2,3-e][1,4]diazepin-2-ylamine ofm.p. 215-217° C. (dec.).

e) A suspension of 9.5 g of7-chloro-5-(2-fluoro-phenyl)-3H-thieno[2,3-e][1,4]diazepin-2-ylamine,4.8 g of 1,3-dichloroacetone, 31.5 g of sodium bicarbonate in 220 ml ofdioxan was stirred at room temperature under argon for 48 h. Thereafter,the temperature was increased to 80° C. and the reaction mixture wasstirred under argon for a further 24 h. After cooling the suspension to60° C. the crude(RS)-2-chloro-8-chloromethyl-4-(2-fluoro-phenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepin-8-olwas used without working up and purification for the step describedbelow.

f) 37.2 g of 2.5N sodium hydroxide solution were added at 60° C. to asuspension of the reaction mixture(RS)-2-chloro-8-chloromethyl-4-(2-fluoro-phenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepin-8-olobtained in accordance with paragraph e) and stirred under argon for 21h., subsequently two 18.7 g portions of 2.5N sodium hydroxide solutionwere added at intervals of two hours and the mixture was stirred for 2h. The suspension was extracted with sodium chloride solution saturatedwith dichloro methane in the presence of a small amount of methanol. Thedichloromethane extracts were dried with sodium sulphate, filtered andevaporated to dryness in a vacuum. After crystallization of the residuefrom 5% methanol in dichloromethane 3.3 g of the starting product ofstep e) were recovered. The mother liquors were evaporated to dryness ina vacuum and the residue was chromatographed on 800 g of silica gel.With 5% methanol in dichloromethane there were eluted 1.5 g of2-chloro-4-(2-fluoro-phenyl)-8,9-dihydro-66H-imidazo[1,2-a]thieno-[3,2-f][1,4]diazepine-8-methanol which was usedwithout further purification as the starting product for the stepdescribed below.

Manufacture ofmethy-2-chloro-4-(2-fluoro-phenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepin-8-yl-acetatehydrochloride

g) 31 drops of perchloric acid (70%) were added to a suspension of 1.5 gof2-chloro-4-(2-fluoro-phenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno-[3,2-f][1,4]diazepine-8-methanolin 31 ml of acetic anhydride until the starting product was completelyin solution. After stirring at room temperature for 20 min. the solutionwas poured into sodium carbonate/ice/dichloromethane and stirred at roomtemperature for 1 h. After extraction the dichloromethane extracts weredried with sodium sulphate, filtered and evaporated to dryness in avacuum. The residue was dried in a high vacuum for 2 h., dissolved in 30ml of acetone, treated with 52 g of 1.6% hydrochloric acid gas indiethyl ether, evaporated in a vacuum (223 mbar) and crystallized fromacetone. After crystallization from acetone there was obtained 1 g ofmethyl[2-chloro-4-(2-fluoro-phenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepin-8-yl-acetate-hydrochlorideof m.p. 126-129° C. (dec., strongly hygroscopic).

EXAMPLE 2 Manufacture of2-chloro-4-(2-fluoro-phenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepine-8-methanolhydrochloride

A solution of 450 mg of methyl(2-chloro-4-(2-fluoro-phenyl)-8,9-dihydro-6H-imidazo[1,2-a]diazepin-8-ylacetate)esterin 15 ml of methanol was treated with 3 ml of 3.5% sodium methanolatesolution in methanol and stirred at room temperature under argon for 15min. The solution was acidified with acetic acid and neutralized with asaturated sodium bicarbonate solution while cooling with ice.Subsequently, the reaction mixture was extracted with dichloromethane.The dichloromethane extract were dried with sodium sulphate, filteredand evaporated to dryness in a vacuum. The residue was dissolved in 15ml of dichloromethane, treated with 27.6 g of 1.5% hydrochloric acid gasin methanol and evaporated in a vacuum (223 mbar). The residue wascrystallized from acetone. There were obtained 243 mg of2-chloro-4-(2-fluorophenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepine-8-methanolhydrochloride of m.p. 142-145° C. (dec., strongly hygroscopic).

EXAMPLE 3 Manufacture of4-phenyl-6H-imidazo[1,2-a]thieno[2,3-f][1,4]diazepine-8-methanoldihydrochloride

a) 5.46 g of potassium tert-butylate were added to a solution of 8.82 gof 5-phenyl-2,3-dihydro-1H-thieno[3,2-e][1,4]diazepin-2-one in 600 ml ofanhydrous tetrahydrofuran and the solution was stirred at roomtemperature for 1 h. and at 50° C. for 1 h. After cooling a solution of12.72 g of dimorpholin-4-yl-phosphine chloride in 300 ml of anhydroustetrahydrofuran and the reaction mixture was stirred at room temperaturefor 20 min. The solution was poured into sodiumbicarbonate/ice/dichloromethane, extracted, the dichloromethane extractswere dried with sodium sulphate, filtered and the organic phase wasevaporated to dryness in a vacuum. After crystallization of the residuefrom diethyl ether/dichloromethane 2 g of the starting product wererecovered. The mother liquors were concentrated and the residue(dimorpholin-4-yl-phosphinic acid5-phenyl-3H-thieno[3,2-e][1,4]-diazepin-2-yl ester) was used withoutfurther purification as the starting product for the step describedbelow.

b) Gaseous ammonia was conducted into a solution of 14.4 g ofdimorpholin-4-yl-phosphinic acid(5-phenyl-3H-thieno[3,2-e][1,4]-diazepin-2-yl) ester at room temperaturewhile stirring until the starting product had reacted completely. Afterremoval of the solvent in a vacuum the residue was extracted withdichloromethane/water in the presence of a small amount of methanol. Theaqueous phase was washed several times with dichloromethane, thedichloromethane extracts were dried with sodium sulphate, filtered andevaporated in a vacuum. The residue was suspended in dichloromethane andstirred for 0.5 h. There were obtained 2.9 g of crude5-phenyl-3H-thieno[3,2-e][1,4]diazepin-2-ylamine which was used withoutfurther purification as the starting product for the step describedbelow.

c) A suspension of 2.9 g of5-phenyl-3H-thieno[3,2-e][1,4]diazepin-2-ylamine, 11.7 g of sodiumbicarbonate and 1.83 g of 1,3-dichloroacetone in 80 ml of dioxan wasstirred at room temperature under argon for 48 h. Thereafter, thetemperature of the reaction mixture was increased to 80° C. and thesuspension was stirred under argon for a further 27 h. After cooling to60° C. 19.2 g of 2.5N sodium hydroxide solution were added and thereaction mixture was stirred under argon for a further 20 h.Subsequently, a further two 19.2 g portions of 2.5N sodium hydroxidesolution were added at intervals of twenty hours. The suspension wasextracted with dichloromethane/saturated sodium chloride solution in thepresence of a small amount of methanol. The dichloromethane extractswere dried with sodium sulphate, filtered and evaporated in a vacuum.The residue was suspended twice in succession in methanol andtriturated. There were obtained 2.14 g of crude4-phenyl-6H-imidazo[1,2-a]thieno[2,3-f][1,4]diazepin-8-ylmethanol whichwas used without further purification as the free base for thepreparation of the dihydrochloride.

200 mg of crude4-phenyl-6H-imidazo[1,2-a]thieno[2,3-f][1,4]-diazepin-8-ylmethanol weredissolved in hot methanol, filtered while hot and treated with 30 g of1.5% hydrochloric acid in methanol and evaporated in a vacuum (223mbar). The residue was crystallized from methanol. There was obtained4-phenyl-6H-imidazo[1,2-a]thieno-[2,3-f][1,4]diazepine-8-methanoldihydrochloride of m.p. >230° C.

EXAMPLE 4 Manufacture of8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

a) 800 ml of aqueous ammonia solution (25%) were added to a solution of27.6 g of 7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2(1H)-thione(J. B. Hester jr., A. D. Rudzik and B. V. Bharat, J.Med. Chem., 1971,14, 1078-1081) in 900 ml of tetrahydrofuran and the mixture was stirredintensively at room temperature for 72 h. The separated organic phasewas concentrated in a vacuum to about 50 ml and the crystals whichthereby separated were filtered off. Drying was carried out in a vacuumat 50° C., firstly over calcium chloride, then over phosphoruspentoxide. There were obtained 22.8 g (87%) of7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamine as a paleyellow crystalline powder of m.p. 248-249° C. (dec.) which was usedwithout further purification for the steps described below.

b) A suspension of 20.0 g of7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamine and 9.72 g of1,3-dichloroacetone in 300 ml of dioxan was treated with 5.84 g ofsodium hydrogen carbonate and heated at reflux for 6 h. Then, 160 ml of1N aqueous sodium hydroxide solution were added dropwise and the mixturewas boiled for a further hour. The reaction mixture was concentrated ina vacuum to a large extent, treated with water and extracted three timeswith equal volumes of dichloromethane. The combined organic phases weredried over magnesium sulphate, concentrated in a vacuum andchromatographed over 1 kg of silica gel. With dichloromethane containing5% methanol there were obtained 11.3 g of the desired product which wasrecrystallized from ethyl acetate/diisopropyl ether. There were thusobtained 10.5 g (44%) of8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolof m.p. 199-201° C.

EXAMPLE 5 Manufacture of8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

a) A suspension of 120 g of7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2(1H)-thione (J. B.Hester jr., A. D. Rudzik and B. V. Bharat, J.Med. Chem., 1971, 14,1078-1081), 150 g of potassium carbonate and 300 ml of iodomethane in2.6 l of acetone was heated at reflux while stirring intensively for 3h. The precipitate was filtered off and the filtrate was concentrated ina vacuum to about ⅓ of the original volume. 500 ml of diethyl ether wereadded while stirring and the precipitate was filtered off. The filtratewas concentrated to dryness and then treated with sufficient acetonesuch that all passed into solution (about 300 ml). 1.5 l of hexane wereadded dropwise while stirring intensively, precipitate7-chloro-5-(2-fluorophenyl)-2-methylthio-3H-1,4-benzodiazepine wasfiltered off, the filtrate was concentrated in a vacuum and, afterdrying in a vacuum at 50° C., 39.2 g were isolated. From theconcentrated mother liquors there were isolated after chromatographicpurification on 500-g of silica gel with ethyl acetate/hexane 1:3 afurther 17.6 g (total yield 45%) of the desired product. This was usedwithout further purification for the step described below.

b) A solution of 22.0 g of7-chloro-5-(2-fluorophenyl)-2-methylthio-3H-1,4-benzodiazepine and 20.0g of L-threonine methyl ester hydrochloride in 200 ml of pyridine wasstirred at 75° C. for 5 h. The solvent was removed in a vacuum and theresidue was purified by chromatography on 800 g of silica gel withdichloromethane containing 5% methanol. There were obtained 16.3 g (59%)of methyl2-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamino]-3-hydroxy-butyrateas a diastereomer mixture which was used without further purification asthe starting product for the step described below.

c) A solution of 3.8 ml of trifluoroacetic acid anhydride in 7.3 ml ofdichloromethane was added dropwise to a solution, cooled with dryice/acetone, of 2.7 ml of dimethyl sulphoxide in 18 ml ofdichloromethane was added in such a manner that the temperature did notexceed −55° C. After stirring in the cold for 30 min. a solution of 7.54g of methyl2-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamino]-3-hydroxybutyratein 15 ml of dichloromethane was added dropwise in a manner such that thetemperature did not exceed −60° C. The mixture was stirred in a dry icebath for 2 h., then brought to −30° C. for 5 min. and subsequently againcooled in a dry ice bath. After the slow addition of 7.5 ml oftriethylamine the mixture was stirred, firstly in the cold for a further30 min., then at room temperature for 30 min. For the working up themixture was extracted with 30 ml of water. The organic phase was driedover magnesium sulphate, concentrated in a vacuum and purified bychromatography on 350 g of silica gel. Byproducts were eluted withdichloromethane containing 1% methanol. With dichloromethane containing3% methanol there were isolated 5.56 g (74%) of methyl2-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamino]-3-oxo-butyratewhich was used without further purification for the step describedbelow.

d) 1.40 g of methyl2-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamino]-3-oxo-butyratewere taken up in 10 ml of dimethylformamide, 100 mg ofp-toluenesulphonic acid monohydrate were added and the mixture wasstirred at 80° C. for 2 h. For the working up the mixture was treatedwith 30 ml of water and extracted 5 times with 50 ml of diethyl ethereach time. The combined organic phases were dried over magnesiumsulphate, concentrated in a vacuum and purified by chromatography on 70g of silica gel with dichloromethane containing 2% methanol. There wereobtained 550 mg (41%) of methyl8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylateof m.p. 137-138° C. which was used without further purification for thestep described below.

e) 3.3 ml of a 1M lithium aluminium, hydride solution in tetrahydrofuranwas cooled to −75° C. and a solution of 1.26 g of methyl 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylatein 15 ml of tetrahydrofuran was added dropwise. After 1 h. in a dryice/acetone bath the mixture was brought to 0° C. and left for a furtherh. For the working up, 0.1 ml of water was added dropwise at 0° C. whilestirring intensively, 0.1 ml of 15% sodium hydroxide solution was addedafter 5 min., finally 0.3 ml of water was added after a further 10 min.After 12 h. the mixture was filtered, the residue was suspended in 100ml of methanol, stirred well for 1 h. and filtered. The combinedfiltrates were concentrated in a vacuum and purified by chromatographyon 80 g of silica gel with dichloromethane containing 5% methanol. Therewere obtained 234 mg (20%) of8-chloro-6-(2-fluoro-phenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol.For the preparation of the methanesulphonic acid salt, 230 mg of thisproduct were dissolved in 10 ml of dichloromethane and 6.0 ml of a 0.1Mmethanesulphonic acid solution in diethyl ether were slowly addeddropwise. After removal of the solvent in a vacuum the residue was takenup in 10 ml of water, filtered and lyophilized. There were isolated 183mg of hygroscopic8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo-[1,2-a][1,4]benzodiazepine-2-methanolmethanesulphonate (1:2) of m.p. 116° C.

EXAMPLE 6 Manufacture of8-chloro-1-diethylaminomethyl-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolhydrochloride (1:1)

a) A suspension of 17.3 g of7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamine, 15.3 g ofdimethyl dihydroxyfumarate (E. F. Hartree, J. Am. Chem. Soc., 1953, 75,6244) and 45.6 g of triphenylphosphine in 350 ml of tetrahydrofuran wascooled to 0° C. and a solution of 26.8 ml of diethyl azodicarboxylate in50 ml of tetrahydrofuran was slowly added dropwise. The mixture wasstirred in the cold for a further 2 h., then stirred at room temperaturefor 10 h. Then, a further 5.0 ml of diethyl azodicarboxylate, 10.0 g oftriphenylphosphine and 5.0 g of dimethyl dihydroxyfumarate were added atroom temperature, the mixture was stirred for 2 h. and finally heatedunder reflux for 5 h. The solvent was removed in a vacuum, the oilyresidue was taken up in 500 ml of methanol and, after the addition of200 ml of 1N sodium hydroxide solution, stirred for 5 days. For theworking up, the methanol was removed at 40° C. to a large extent and theresidue was extracted with 300 ml of ethyl acetate. The aqueous phasewas brought to pH 3 with 10% aqueous hydrochloric acid and theprecipitate which separated was filtered off, dried and there were thusisolated 16.2 g (66%) of8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-1,2dicarboxylic acid 1-methyl ester. This was used without furtherpurification as the starting product for the step described below.

b) 13.0 g of8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]-benzodiazepine-1,2-dicarboxylicacid 1-methyl ester were taken up in 100 ml of tetrahydrofuran, 1 ml ofdimethylformamide was added and 7.0 ml of oxalyl chloride were slowlyadded dropwise at 0° C. After the completion of the addition the mixturewas stirred at room temperature for a further 30 min. Then, a mixture of25 ml of pyridine and 25 ml of methanol were added dropwise whilecooling in such a manner that the temperature did not exceed 10° C.Subsequently, the mixture was stirred at room temperature for a further1 h. For the working up, all volatiles were removed in an oil pumpvacuum, the residue was taken up with 200 ml of dichloromethane andextracted with 200 ml of water. The organic phase was dried overmagnesium sulphate, concentrated in a vacuum and brought tocrystallization by trituration with diethyl ether. After drying in ahigh vacuum at 50° C. there were thus obtained 12.1 g (90%) of dimethyl8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]-benzodiazepine-1,2-dicarboxylateof m.p. 206-207° C. which was used directly without further purificationfor the next step.

c) A solution of 7.29 g of dimethyl8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-1,2-dicarboxylatein 100 ml of tetrahydrofuran was cooled to −78° C. and20 ml of a 1Mlithium aluminium hydride solution in tetrahydrofuran was added dropwisein a manner such that the temperature did not exceed −70° C. Aftercompletion of the addition the mixture was brought slowly to roomtemperature and stirred for 1 h. Then, it was treated dropwise withsaturated sodium potassium tartrate solution and stirred well for 12 h.The insoluble material was filtered off, the filtrate was concentratedand the residue was recrystallized from isopropanol. The concentratedmother liquor was purified by chromatography on 300 g of silica gel withdichloromethane/methanol/glacial acetic acid 90:10:2 and the fractionscontaining the product, after removal of the solvent, were againrecrystallized from isopropanol. There were thus isolated a total of 4.1g (65%) of[8-chloro-6-(2-fluorophenyl)-2-hydroxymethyl-4H-imidazo[1,2-a]-[1,4]benzodiazepin-1-yl]-methanolof m.p. 222° C.

d) A solution of 7.29 g of tert-butyldimethylsilyl chloride in 15 ml ofdimethyl formamide was added dropwise to a solution, cooled to 0° C., of15.0 g of[8-chloro-6-(2-fluorophenyl)-2-hydroxymethyl-4H-imidazo[1,2-a]-[1,4]benzodiazepin-1-yl]-methanoland 3.29 g of imidazole in 50 ml of dimethyl formamide. The mixture wasbrought to room temperature and stirred at room temperature for 12 h.For the working up, the solvent was removed in an oil pump vacuum at 40°C. and the residue was taken up with 500 ml of water and 500 ml ofdichloromethane. The aqueous phase was again extracted with equalvolumes of dichloromethane and the combined organic phases were driedover magnesium sulphate. After removal of the solvent in a vacuum theresidue remaining behind was purified by chromatography on 500 g ofsilica gel with a dichloromethane/methanol mixture 98:2. Afterrecrystallization from diethyl ether/hexane there were thus obtained14.4 g (74%) of2-(tert-butyl-dimethyl-silanyloxymethyl)-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-1-methanolof m.p. 172° C. This was used without further purification as thestarting product for the steps described below.

e) 820 mg of tetrabromomethane and 650 mg of triphenylphosphine wereadded in succession and portionwise to a solution of 1.0 g of2-(tert-butyl-dimethyl-silanyloxymethyl)-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-1-methanolin 10 ml of tetrahydrofuran. After stirring at room temperature for 2 h.a further 160 mg of tetrabromomethane and 130 mg of triphenylphosphinewere added and the mixture was stirred for a further 2 h. Subsequently,the solvent was removed at 40° C. in a vacuum and the residue wastriturated twice with 10 ml of ethyl acetate each time and filtered off.2.0 ml of diethylamine were added to the combined filtrates and thisreaction mixture was stirred at 50° C. for 10 h. Then, all volatileswere removed in an oil pump vacuum at 40° C., the residue was taken upwith 5 ml of tetrahydrofuran and 10 ml of 1N hydrochloric acid andstirred at room temperature for 3 h. After the addition of 30 ml ofethyl acetate the separated organic phase was again extracted with 10 mlof 1N hydrochloric acid. The combined aqueous phases were treated with10 ml of 2N sodium hydroxide solution and extracted three times with 30ml of ethyl acetate each time. Drying of the organic phase overmagnesium sulphate and removal of the solvent in a vacuum left behind850 mg of crude product which was purified by chromatography on 80 g ofsilica gel with a mixture of dichloromethane/methanol/ammonium hydroxide140:10:1. There were thus obtained 740 mg (84%) of8-chloro-1-diethylaminomethyl-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolas a crystalline foam. The m.p. lay at 159° C. after recrystallizationfrom diethyl ether. For the preparation of the hydrochloride, 280 mg ofthis product were dissolved in 10 ml of dioxan and 6.23 ml of 0.1Nhydrochloric acid were added dropwise. The mixture was lyophilized,taken up with 10 ml of water, filtered and again lyophilized and therewas thus obtained8-chloro-1-diethylaminomethyl-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolhydrochloride (1:1) of m.p. 130° C. (dec.).

EXAMPLE 7 Manufacture of8-chloro-6-(2-fluorophenyl)-1-morpholin-4-ylmethyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolhydrochloride (1:1)

820 mg of tetrabromomethane and 650 mg of triphenylphosphine were addedin succession and portionwise to a solution of 1.0 g of[2-(tert.-butyl-dimethylsilanyloxymethyl)-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-1-yl]-methanolin 10 ml of tetrahydrofuran. After stirring at room temperature for 2 h.a further 160 mg of tetrabromomethane and 130 mg of triphenylphosphinewere added and the mixture was stirred for a further 2 h. Subsequently,the solvent was removed at 40° C. in a vacuum, the residue wastriturated twice with 10 ml of ethyl acetate each time and filtered off.2.0 ml of morpholine were added to the combined filtrates and thisreaction mixture was stirred at 50° C. for 2 h., then all volatiles wereremoved in an oil pump vacuum at 40° C., the residue was taken up with 5ml of tetrahydrofuran and 10 ml of 1N hydrochloric acid and stirred atroom temperature for 3 h. After the addition of 30 ml of ethyl acetatethe separated organic phase was again extracted with 10 ml of 1Nhydrochloric acid. The combined aqueous phases were treated with 10 mlof 2N sodium hydroxide solution and extracted three times with 30 ml ofethyl acetate each time. Drying of the organic phase over magnesiumsulphate and removal of the solvent in a vacuum yielded 800 mg of crudeproduct which was purified by chromatography on 50 g of silica gel witha mixture of dichloromethane/methanol/ammonium hydroxide 140:10:1. Therewere thus isolated 560 mg (62%) of8-chloro-6-(2-fluorophenyl)-1-morpholin-4-ylmethyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolas a crystalline foam. After recrystallization fromdichloromethane/diethyl ether the m.p. lay at 216° C. For thepreparation of the hydrochloride, 243 mg (0.551 mmol) of this productwere dissolved in 10 ml of dioxan and 5.22 ml of 0.1N hydrochloric acidwere added dropwise. The mixture was lyophilized, taken up with 10 ml ofwater, filtered and again lyophilized and there was thus obtained8-chloro-6-(2-fluorophenyl)-1-morpholin-4-ylmethyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolhydrochloride (1:1) of m.p. 155° C. (dec.).

EXAMPLE 8 Manufacture of8-chloro-6-(2-fluorophenyl)-1-methylaminomethyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolhydrochloride (1:1)

820 mg of tetrabromomethane and 650 mg of triphenylphosphine were addedin succession and portionwise to a solution of 1.0 g of[2-(tert.-butyl-dimethyl-silanyloxymethyl)-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-1-yl]methanolin 10 ml of tetrahydrofuran. After stirring at room temperature for 2 h.a further 160 mg of tetrabromomethane and 130 mg of triphenylphosphinewere added and the mixture was stirred for a further 2 h. Subsequently,the solvent was removed at 40° C. in a vacuum and the residue wastriturated twice with 10 ml of ethyl acetate each time and filtered off.The combined filtrates were added to 50 ml of a tetrahydrofuran solutionsaturated with methylamine at 0° C. and this reaction mixture wasstirred at room temperature for 3 h. Then, all volatiles were removed inan oil pump vacuum at 40° C., the residue was taken up with 5 ml oftetrahydrofuran and 10 ml of 1N hydrochloric acid and stirred at roomtemperature for 3 h. After the addition of 30 ml of ethyl acetate theseparated organic phase was again extracted with 10 ml of 1Nhydrochloric acid. The combined aqueous phases were treated with 10 mlof 2N sodium hydroxide solution and extracted three times with 30 ml ofethyl acetate each time. Drying of the organic phase over magnesiumsulphate and removal of the solvent in a vacuum yielded 600 mg of crudeproduct which was purified by chromatography on 50 g of silica gel witha mixture of dichloromethane/ methanol/ammonium hydroxide 200:10:1. 290mg (37%) of8-chloro-6-(2-fluorophenyl)-1-methylaminomethyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolwere isolated as a crystalline foam. After recrystallization fromdichloromethane/diethyl ether the m.p. lay at 172° C. For thepreparation of the hydrochloride, 196 mg (0.509 mmol) of this productwere dissolved in 5 ml of dioxan and 4.85 ml of 0.1N hydrochloric acidwere added dropwise. The mixture was lyophilized, taken up with 20 ml ofwater, filtered and again lyophilized and there was thus isolated8-chloro-6-(2-fluorophenyl)-1-methylaminomethyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolhydrochloride (1:1) of m.p. 1500° C. (dec.).

EXAMPLE 9 Manufacture of1-allylaminomethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolhydrochloride (1:1)

3.07 g of tetrabromomethane and 2.43 g (9.3 mmol) of triphenylphosphinewere added in succession and portionwise to a solution of 3.0 g of[2-(tert.-butyl-dimethylsilanyloxymethyl)-8-chloro-6-(2-fluoro-phenyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-1-yl]methanolin 10 ml of tetrahydrofuran. After stirring at room temperature for 3 h.the mixture was filtered and the residue was rinsed with a small amountof tetrahydrofuran. 25 ml (333 mmol) of allylamine were added to thefiltrate and this reaction mixture was stirred at 50° C. for 2 h. Then,all volatiles were removed at 40° C. in an oil pump vacuum, the residuewas taken up with 30 ml of tetrahydrofuran and 30 ml of 1N hydrochloricacid and stirred at room temperature for 3 h. After the addition of 100ml of ethyl acetate the separated organic phase was again extracted with30 ml of 1N hydrochloric acid. The combined aqueous phases were treatedwith 30 ml of 2N sodium hydroxide solution and extracted three timeswith 100 ml of ethyl acetate each time. Drying of the organic phase overmagnesium sulphate and removal of the solvent in a vacuum yielded 2.6 gof crude product which was purified by chromatography on 300 g of silicagel with a mixture of dichloromethane/methanol/ammonium hydroxide200:10:1. 1.96 g (77%) of1-allylaminomethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol were thus isolated as acrystalline foam. After recrystallization from dichloromethane/diethylether the melting point lay at 173° C. For the preparation of thehydrochloride, 776 mg of this product were dissolved in 30 ml of dioxanand 18.9 ml of 0.1N hydrochloric acid were added dropwise. The mixturewas lyophilized, taken up with 10 ml of water, filtered, againlyophilized and there was thus obtained1-allylaminomethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolhydrochloride (1:1) of m.p. 140° C.

EXAMPLE 10 Manufacture of8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

a) To a suspension of 32.3 g of7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2(1H)-thione (J. B.Hester jr., A. D. Rudzik and B. V. Bharat, J-Med. Chem., 1971, 14,1078-1081) in 900 ml of butanol were added 17.2 g of3,3-diethoxy-1-hydroxy-2-propylamine (S. David and A. Veyrieres,Carbohyd. Res. 1969, 10, 35-38) and the mixture was heated at refluxwhile stirring for 24 h. The solvent was then removed in a vacuum. Theresidue (55 g of red oil) was dissolved in a 1:1 mixture of ethylacetate and hexane and chromatographed over 700 g of silica gel. Withethyl acetate/hexane 1:1 and 3:1 there were firstly eluted about 8 g ofa byproduct and then with ethyl acetate/hexane 9:1 30.8 g of7-chloro-2-(3,3-diethoxy-1-hydroxy-2-propylamino)-5-(2-fluorophenyl)-3H-1,4-benzodiazepinewhich was used without further purification as the starting product forthe step described below.

b) A solution of 30 g of7-chloro-2-(3,3-diethoxy-1-hydroxy-2-propyl-amino)-5-(2-fluorophenyl)-3H-1,4-benzodiazepinein 300 ml of glacial acetic acid was heated to reflux temperature for 5h. After cooling the solvent was removed in a vacuum, the residue wastaken up in 300 ml of ethanol, the solution was treated with 150 ml of2N aqueous sodium hydroxide solution and left te stand at roomtemperature for 2 h. Then, about 200 ml of ethanol were distilled off at30° C. in a vacuum. The solution remaining behind was extracted threetimes with chloroform. The chloroform extracts were washed withsaturated sodium chloride solution, then dried over sodium sulphate andevaporated to dryness in a vacuum. The residue (20.5 g) was dissolved inchloroform and chromatographed over 500 g of silica gel. Byproducts(total 4.1 g) were eluted with chloroform containing 0.2% to 1.6%ethanol. 13.0 g of the desired product were eluted with chloroformcontaining 2.4 to 20% ethanol. After recrystallization from ethylacetate/diethyl ether there were obtained 11.6 g of8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolof m.p. 196-199.5° C. After repeated recrystallization from ethylacetate the m.p. lay at 199-201° C.

EXAMPLE 11 Manufacture of8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

A solution of 9.1 g of2-amino-7-chloro-5-(2-chlorophenyl)-3H-1,4-benzodiazepine (K. Meguro, H.Tawada & Y. Kuwada, Yakugaku Zasshi, 1973, 93, 1253-1262) and 11.4 g of1,3-dichloroacetone in 195 ml of dioxan was treated with 24.9 g ofanhydrous potassium carbonate and stirred at 98° C. for 22 h. Aftercooling the inorganic salts were filtered off, the filtrate was treatedwith 0.75 g of p-toluenesulphonic acid and stirred at 98° C. for 2.5 h.60 ml of 1N aqueous sodium hydroxide solution and 2.0 g of activecharcoal were added to this solution and the mixture was stirred at 80°C. for 2.5 h. After cooling the mixture was filtered and the filtratewas concentrated in a vacuum. The residue was taken up in 300 ml ofdichloromethane and the solution was shaken with 200 ml of 6N aqueoushydrochloric acid. The crystals which thereby separated were filteredoff (4.2 g) and the filtrate was extracted a further three times with200 ml of 6N aqueous hydrochloric acid each time The combined aqueousextracts were made weakly basic (pH 8 to 9) with aqueous sodiumhydroxide solution and the precipitate was filtered off. The filter caketogether with the crystals (4.2 g) filtered off earlier were taken up inchloroform and in 2N aqueous sodium hydroxide solution, the mixture wasfiltered clear and the aqueous phase is extracted a further twice withchloroform. The chloroform extracts were dried over sodium sulphate,concentrated in a vacuum to 100 ml and chromatographed over 210 g ofsilica gel. A small amount of byproduct was eluted with chloroform. Thedesired product was eluted with chloroform containing 1 to 4% ethanoland was crystallized from ethyl acetate. There were obtained 3.8 g of8-chloro-6-(2-chlorophenyl)-4H-imidazo-[1,2-a][1,4]benzodiazepine-2-methanolof m.p. 174-175° C., which was converted into the hydrochloride, m.p.257-259° C.

EXAMPLE 12 Manufacture of8-chloro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

A solution of 10.9 g of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine(K. Meguro, H. Tawada & Y. Kuwada, Yakugaku Zasshi, 1973, 93, 1253-1262)and 5.2 g of 1,3-dichloroacetone in 200 ml of dioxan was treated with3.13 g of anhydrous sodium hydrogen carbonate and stirred at 98° C. for22 h. After cooling the inorganic salts were filtered off, the filtratewas treated with 0.93 g of p-toluenesulphonic acid and stirred at 98° C.for 1.5 h. 74.5 ml of 1N aqueous sodium hydroxide solution and 2.5 g ofactive charcoal were added to this solution and the mixture was stirredat 80° C. for 2 h. After cooling the mixture was filtered over Dicaliteand the filtrate was concentrated in a vacuum. The residue was taken upin dichloromethane and water and the aqueous phase was extracted fourtimes with chloroform. The chloroform was evaporated in a vacuum. Theresidue (about 8 g) was crystallized from ethyl acetate. The crystals(7.3 g) were filtered off, dissolved in dichloromethane andchromatographed over 180 g of silica gel. The desired product was elutedwith dichloromethane containing 2 to 4% ethanol and was recrystallizedfrom ethyl acetate/ethanol 2:1. There were obtained 3.4 g of8-chloro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol ofm.p. 203-204° C., which was converted into the hydrochloride, m.p.252-254° C.

EXAMPLE 13 Manufacture of8-trifluoromethyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

A solution of 10.5 g of2-amino-7-trifluoromethyl-5-phenyl-3H-1,4-benzodiazepine (K. Meguro, H.Tawada & Y. Kuwada, Yakugaku Zasshi, 1973, 93, 1253-1262) and 4.84 g of1,3-dichloroacetone in 220 ml of dioxan was treated with 2.72 g ofanhydrous sodium hydrogen carbonate and stirred at 98° C. for 16 h.After cooling the inorganic salts were filtered off, the filtrate wastreated with 0.75 g of p-toluenesulphonic acid and stirred at 98° C. for2 h. 60 ml of 1N aqueous sodium hydroxide solution were added to thissolution and the mixture was stirred at 80° C. for 3 h. After coolingthe mixture was concentrated in a vacuum. The residue was taken up inchloroform and water and the aqueous phase was extracted a further fourtimes with chloroform. The chloroform was evaporated in a vacuum. Theresidue was recrystallized twice from ethyl acetate. There were obtained3.15 g of8-trifluoromethyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolof m.p. 193-194° C., which was converted into the hydrochloride of m.p.252-254° C.

EXAMPLE 14 Manufacture of6-(2-fluorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

a) A solution of 20.0 g of5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepin-2(1H)-one (G. M. Clarke,J. B. Lee, F. J. Swinbourne & B. Williamson, J. Chem. Res. Synop. 1980,400) in 100 ml of hexamethylphosphoric acid triamide was treated with 14g of Lawesson reagent and the mixture was stirred at 105° C. for 70 min.The reaction mixture was poured into 800 ml of saturated aqueous sodiumhydrogen carbonate solution and 800 ml of water. After stirring at roomtemperature for 15 min. the precipitate was filtered off, washed withwater and dried. There were obtained 20 g of crude5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepine-2(1H)-thione, which wasused in this form for the next step.

A sample of pure5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepine-2(1H)-thione of m.p.218-220° C. was obtained by the chromatography of 2 g of crude materialover 50 g of silica gel, elution with dichloromethane andrecrystallization from ethyl acetate.

b) 350 ml of 25% aqueous ammonia solution were added to a solution of 20g of 5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepine-2(1H)-thione in 1l of tetrahydrofuran. The solution was stirred at room temperature for20 h. and then concentrated to 200 ml in a vacuum. The crystallineprecipitate was filtered off (12.1 g) and the filtrate was concentratedto 50 ml. A further 3.1 g of crystals could be filtered off. Total yield15.2 g of 2-amino-5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepine ofm.p. 225-227° C.

c) A solution of 14.9 g of2-amino-5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepine and 7.65 g of1,3-dichloroacetone in 300 ml of dioxan was treated with 5.05 g ofanhydrous sodium hydrogen carbonate and stirred at 98° C. for 16 h. Afurther 1.53 g of 1,3-dichloroacetone and 1.0 g of anhydrous sodiumhydrogen carbonate were added and the mixture was stirred at 98° C. fora further 4 h. After cooling the inorganic salts were filtered off, thefiltrate was treated with 1.5 g of p-toluenesulphonic acid and themixture was stirred at 98° C. for 2 h. Then, the mixture wasconcentrated in a vacuum and the residue was partitioned betweenchloroform and water. The chloroform phase was washed with water, driedover sodium sulphate and evaporated in a vacuum. The oily residue wasdissolved in dichloromethane and chromatographed over 600 g of silicagel. With dichloromethane/ethanol 99:1 there were eluted 13 g of oily2-chloromethyl-6-(2-fluorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepinewhich was used for the next step.

The hydrochloride, m.p. 251-253° C., was obtained by reaction withanhydrous hydrochloric acid in ethyl acetate.

A solution of 12 g of2-chloromethyl-6-(2-fluorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine in 100 ml of dioxan was treated with asolution of 3.5 g of sodium carbonate in 50 ml of water and stirred at80° C. for 2.5 h. Then, the mixture was made weakly acidic (pH 6 to 7)with aqueous 3N hydrochloric acid and evaporated in a vacuum. Theresidue was taken up in chloroform, washed twice with water, dried oversodium sulphate and evaporated in a vacuum. The residue was dissolved inchloroform and chromatographed over 250 g of silica gel. Withchloroform/ethanol 98:2 there were isolated a small amount ofimpurities, with chloroform/,6thanol 98:2 there was eluted6-(2-fluorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol.After recrystallization from chloroform there were obtained 5.8 g of6-(2-fluorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolof m.p. 230-231° C. This was converted into the hydrochloride of m.p.239-241° C.

EXAMPLE 15 Manufacture of6-(2-chlorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

a) To a solution of 14 g of5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepine-2(1H)-thione (J. B.Hester, A. D. Rudzik & B. V. Kamdar, J. Med. Chem., 1971, 14, 1078-1081)in 700 ml of tetrahydrofuran were added firstly 260 ml of 25% aqueousammonia solution and then 50 ml of methanol. The solution was stirred atroom temperature for 20 h. and then concentrated to about 25 ml in avacuum. The crystalline precipitate was filtered off and recrystallizedfrom dioxan. There were obtained 13.2 g of2-amino-5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepine of m.p.222-224° C.

b) A solution of 3.14 g of2-amino-5-(2-chlorophenyl)-7-nitro-3H-1,4benzodiazepine and 1.39 g of1,3-dichloroacetone in 100 ml of dioxan was treated with 0.925 g ofanhydrous sodium hydrogen carbonate and stirred at 98° C. for 20 h.Then, a further 0.28 g of 1,3 dichloroacetone and 0.23 g of anhydroussodium hydrogen carbonate were added and the mixture was stirred at 98°C. for 3 h. After cooling the inorganic salts were filtered off, thefiltrate was treated with 0.23 g of p-toluenesulphonic acid and stirredat 98° C. for 2 h. The solution was decolorized with active charcoal andfiltered over Dicalite. The filtrate was concentrated in a vacuum, theresidue was dissolved in dichloromethane and chromatographed over 65 gof silica gel. With dichloromethane there was eluted an impurity, withdichloromethane/ethanol 99:1 there were eluted 2.7 g of2-chloromethyl-6-(2-chlorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepinewhich was used without further purification for the further reaction.

A solution of 2.7 g of2-chloromethyl-6-(2-chlorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine in 30 ml of dioxan was treated with asolution of 0.74 g of sodium hydrogen carbonate in 10 ml of water andthe mixture was stirred at 80° C. for 2.5 h. The mixture was filteredand the filtrate was made neutral with aqueous 3N hydrochloric acid. Thefiltrate was evaporated in a vacuum and the residue was taken up inchloroform and water. The chloroform phase was washed with water, driedover sodium sulphate and evaporated in a vacuum. The residue wascrystallized in 30 ml of ethyl acetate and diethyl ether and filtered.The crystals were dissolved in dichloromethane and chromatographed over75 g of silica gel. With dichloromethane/ ethanol 99:1, 98:2 and 97:3there were eluted small amounts of different impurities, withdichloromethane/ethanol 95:5 there was eluted6-(2-chlorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol.After recrystallization from ethyl acetate there were obtained 1.4 g ofpure6-(2-chlorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolof m.p. 173-174° C. which was converted into the methane-sulphonate(m.p. 211-212° C.).

EXAMPLE 16 Manufacture of8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

a) 300 ml of 25% aqueous ammonia solution were added to a solution of 16g of 7-nitro-5-phenyl-3H-1,4-benzodiazepine-2(1H)-thione (J. B. Hester,A. D. Rudzik & B. V. Kamdar, J.Med.Chem., 1971, 14, 1078-1081) in 850 mlof tetrahydrofuran. The solution was stirred at room temperature for 20h. and then concentrated to about 50 ml in a vacuum. The crystallineprecipitate was filtered off and recrystallized from dioxan. There wereobtained 8.0 g of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine whichwas used in this form for the next step.

b) A solution of 8.0 g of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepineand 4.34 g of 1,3-dichloroacetone in 200 ml of dioxan was treated with2.76 g of anhydrous sodium hydrogen carbonate and stirred at 98° C. for20 h. Then, a further 0.28 g of 1,3-dichloroacetone and 0.23 g ofanhydrous sodium hydrogen carbonate were added and the mixture wasstirred at 980° C. for 3 h. After cooling the inorganic salts werefiltered off, the filtrate was treated with 0.65 g of p-toluenesulphonicacid and stirred at 98° C. for 1 h. The solution was decolorized withactive charcoal and filtered through Dicalite. The filtrate wasconcentrated in a vacuum, the residue was dissolved in chloroform, thechloroform extracts were washed three times with water, then dried oversodium sulphate and chromatographed over 500 g of silica gel. Withdichloro methane there was eluted an impurity, withdichloromethane/ethanol 99:1 there were eluted 5.1 g of2-chloromethyl-8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepinewhich was used without further purification for the further reaction.

A solution of 5.1 g of2-chloromethyl-8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine in70 ml of dioxan was treated with a solution of 1.54 g of sodium hydrogencarbonate in 30 ml of water and the mixture was stirred at 80° C. for2.5 h. The mixture was filtered and the filtrate was made weakly acidic(pH 6 to 7) with aqueous 3N hydrochloric acid. The filtrate wasevaporated in a vacuum and the residue was taken up in chloroform andwater. The chloroform phase was washed with water, dried over sodiumsulphate and evaporated in a vacuum. The crystalline residue (3.2 g) wasdissolved in chloroform and chromatographed over 130 g of silica gel.With chloroform and with chloroform/ethanol 98:2 there were eluted smallamounts of various impurities, with chloroform/ethanol 97:3 and 96:4there was eluted8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol. Afterrecrystallization from ethanol there were obtained 2.45 g of pure8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p.250-251° C. which was converted into the hydrochloride (m.p. 295-297°C.).

EXAMPLE 17 Manufacture of6-(2-fluorophenyl)-8-iodo-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

a) 50 ml of 25% aqueous ammonia solution were added to a solution of 2.3g of 5-(2-fluorophenyl)-7-iodo-3H-1,4-benzodiazepine-2(1H)-thione (A.Walser, T. Flynn, C. Mason, H. Crowley, C. Maresco, B. Yaremko & M.O'Donell, J.Med.Chem., 1991, 34, 1209) in 120 ml of tetrahydrofuran.After the addition of 5 ml of methanol the solution was stirred at roomtemperature for 24 h. and then evaporated in a vacuum. The residue waspartitioned between saturated aqueous sodium hydrogen carbonate solutionand chloroform. The aqueous phase was extracted a further three timeswith chloroform. The chloroform extracts were dried over sodium sulphateand evaporated in a vacuum. The residue was recrystallized from ethylacetate. There were obtained 2.73 g of 2-amino-7-iodo-5-(2-fluorophenyl)-3H-1,4-benzodiazepine of m.p. 219-221° C.

b) A solution of 1.65 g of2-amino-7-iodo-5-(2-fluorophenyl)-3H-1,4-benzodiazepine and 0.67 g of1,3-dichloroacetone in 23 ml of dioxan was treated with 0.44 g ofanhydrous sodium hydrogen carbonate and the mixture was stirred at 98°C. for 20 h. After cooling the inorganic salts were filtered off, thefiltrate was treated with 0.35 g of p-toluenesulphonic acid and stirredat 98° C. for 2 h. The solution was decolorized with active charcoal andfiltered over Dicalite. The filtrate was concentrated in a vacuum, theresidue was dissolved in chloroform, the chloroform solution was washedthree times with water, then dried over sodium sulphate andchromatographed over 50 g of silica gel. With dichloromethane there waseluted an impurity, with dichloromethane/ethanol 99:1 there were eluted1.2 g of 2-chloromethyl-6-(2-fluorophenyl)-8-iodo-4H-imidazo[1,2-a][1,4]benzodiazepine which was used without further purificationfor the further reaction.

A solution of 1.2 g of2-chloromethyl-6-(2-fluorophenyl)-8-iodo-4H-imidazo[1,2-a][1,4]benzodiazepine in 20 ml of dioxan was treated with asolution of 0.4 g of sodium hydrogen carbonate in 10 ml of water and themixture was stirred at 80° C. for 2 h. The mixture was filtered and thefiltrate was made weakly acidic (pH 6 to 7) with aqueous 3N hydrochloricacid. The filtrate was evaporated in a vacuum and the residue was takenup in chloroform and water. The chloroform phase was washed with water,dried over sodium sulphate and evaporated in a vacuum. The residue wasrecrystallized from ethanol. There was obtained 0.6 g of amorphous6-(2-fluorophenyl)-8-iodo-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolwhich was converted into the crystalline hydrochloride (m.p. 274-276°C.),

EXAMPLE 18 Manufacture of8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

a) 59.5 g of 7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione(J. B. Hester, jr., A. D. Rudzik & P.F . Von Voigtlander, J. Med. Chem.,1980,23, 392-402) in 800 ml of tetrahydrofuran were added to 1.0 l of25% aqueous ammonia solution and 300 ml of methanol. The mixture wasstirred at room temperature for 16 h., with the solution which formedbeing concentrated to about 500 ml in a vacuum. The crystals werefiltered off, washed with water and dried. There were obtained 52 g of2-amino-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine which was usedwithout further purification for the next step. A sample recrystallizedfrom dioxan melted at 213-215° C. (dec.).

b) A suspension of 52 g of2-amino-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine in 1.5 l oftetrahydrofuran was treated in succession with 58 ml ofN-ethyldiisopropylamine and 44 ml of ethyl bromopyruvate and the mixturewas stirred at 65° C. for 20 min. Then, a further 5.8 ml ofN-ethyldiisopropylamine and 44 ml of ethyl bromopyruvate were added andthe mixture was stirred at 65° C. for a further 20 min. After cooling inan ice bath 0.5 l of diethyl ether was added and the crystals werefiltered off. 49.5 g of N-ethyldiisopropylamine hydrobromide wereobtained. The filtrate was evaporated in a vacuum, the residue was takenup in dichloromethane and shaken twice with saturated aqueous sodiumhydrogen carbonate solution. The organic phase was dried over sodiumsulphate and chromatographed over 2 kg of silica gel. Withdichloromethane/ethanol 197:3 and 196:4 there were firstly eluted smallamounts of impurities, then with dichloromethane/ethanol 97:3, 95:5 and94:6 there were isolated a total of 58.2 g of ethyl3-[2-amino-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-1-yl]pyruvate.This was dissolved in 11 of acetic acid and stirred at 100° C. for 3.5h. The solution was then evaporated in a vacuum and the residue waspartitioned between dichloromethane and saturated aqueous sodiumhydrogen carbonate solution (11 of each). The dichloromethane phase wasseparated, dried over sodium sulphate and chromatographed over 2 kg ofsilica gel. 17.2 g of ethyl8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylatewere obtained as dark red crystals by elution with ethyl acetate. Thiswas again chromatographed over 2 kg of silica gel. Strongly colouredimpurities were eluted with ethyl acetate/dichloromethane 1:1 and 2:1.The desired ethyl8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylatewas eluted with ethyl acetate. There were obtained 11.7 g of ethyl8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylateof m.p. 227-230° C.

c) 0.38 g of lithium aluminium hydride was added portionwise to asuspension of 2.06 g of ethyl8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylatein 250 ml of tetrahydrofuran at −40° C. while stirring vigorously. Adark green solution thereby formed and this was stirred at −7 to −10° C.for 45 min. Then, the mixture was cooled to −35° C. and treated dropwisewith 2 ml of water. After stirring at room temperature for 2 h. afurther 6.0 ml of water were added slowly. The reaction mixture wasfiltered clear over Dicalite and the filtrate was evaporated in avacuum. The residue was partitioned between 100 ml of chloroform and 50ml of saturated aqueous sodium hydrogen carbonate solution. Thechloroform phase was separated, dried over sodium sulphate andevaporated in a vacuum. The residue (1.9 g) was dissolved in 100 ml oftert-butanol and 50 ml of pyridine, treated with 1.0 g of seleniumdioxide and stirred at 65° C. for 30 min. The mixture was evaporated ina vacuum, the residue was dissolved in chloroform, with a small amountof insoluble impurity being filtered off. The solution waschromatographed over 250 g of aluminium oxide (activity 1). A smallamount of impurity was eluted with dichloromethane/etanol 98:2, then0.95 g of the desired8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolwas eluted with dichloromethane/ethanol 95:5, 90:10 and 80:20. Afterrecrystallization from ethyl acetate there was obtained 0.80 g of8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol ofm.p. 176-178° C. which was converted into the hydrochloride (m.p. above300° C.).

EXAMPLE 19 Manufacture of8-chloro-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

a) A solution of 18.5 g of7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepin-2(1H)-one (N. Ch. Hindley,T. M. McClymont & G. O. Chase; F. Hoffmann La Roche and Co., A. G.,German Offenlegungsschrift 2,233,483, 1973) in 150 ml of pyridine wastreated with 14.2 g of Lawesson reagent and the mixture was stirred at100° C. for 2 h. After the addition of 1.0 g of Lawesson reagent themixture was stirred at 100° C. for a further 0.5 h. and then evaporatedin a vacuum. The residue was poured into 500 ml of saturated aqueoussodium hydrogen carbonate solution and the precipitate was filtered off(22 g). The red crystals were suspended in 100 ml of boiling methanol.After cooling 100 ml of diethyl ether were added and the crystals werefiltered off. There were obtained 18.7 g of7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione of m.p.217-218° C.

b) 300 ml of 25% aqueous ammonia solution and 100 ml of methanol wereadded to a solution of 18.5 g of7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione in 800 ml oftetrahydrofuran. The mixture was stirred at room temperature for 17 h.,with the solution which formed being concentrated to about 200 ml in avacuum. The crystals were filtered off, washed with water and dried,stirred in 25 ml of dioxan at 100° C., cooled and filtered off. Therewere obtained 16.3 g of2-amino-7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepine which was usedwithout further purification for the next step. A sample recrystallizedfrom dioxan melted at 213-215° C.

c) A solution of 16.3 g of2-amino-7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepine and 8.4 g of1,3-dichloroacetone in 600 ml of dioxan was treated with 5.6 g ofanhydrous sodium hydrogen carbonate and stirred at 100°0 C. for 16 h. Afurther 0.84 g of dichloroacetone and 0.56 g of anhydrous sodiumhydrogen carbonate were added and the mixture was stirred at 100° C. fora further 8 h. The mixture was evaporated in a vacuum and the residuewas partitioned between chloroform and water. The aqueous phase wasextracted twice with dichloromethane. The combined organic phases wereevaporated in a vacuum. The residue was dissolved in dichloromethane andchromatographed over 800 g of silica gel. With dichloromethane/ethanol197:3 there were eluted small amounts of impurities, withdichloromethane/ethanol 196:4 there were eluted 10.2 g of the desiredproduct. After recrystallization from ethyl acetate there were obtained9.0 g of2-chloromethyl-8-chloro-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepineof m.p. 161° C.

d) A solution of 2.0 g of2-chloromethyl-8-chloro-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine in 50 ml of dioxan was treated with asolution of 0.62 g of sodium hydrogen carbonate in 18 ml of water andthe mixture was stirred at 80° C. for 1.5 h. The mixture was evaporatedin a vacuum. The residue was partitioned between dichloromethane andaqueous sodium hydrogen carbonate solution. The aqueous phase wasextracted twice with dichloromethane. The dichloromethane extracts weredried over magnesium sulphate and chromatographed over 100 g of silicagel. 1.7 g of the desired product were eluted withdichloromethane/ethanol mixtures containing 8 to 12% ethanol. Afterrecrystallization from ethyl acetate/diethyl (sic) ether there wereobtained 1.65 g of8-chloro-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolof m.p. 206-207° C., which was converted into the hydrochloride (dec.above 300° C.).

EXAMPLE 20 Manufacture of8-iodo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

a) To a suspension of 18.7 g of 2-(2-amino-5-iodobenzoyl)pyridine (R. I.Fryer, P. Zhang & R. Rios, Synth.Commun. 1993, 23, 985-992) in 760 ml ofbenzene were added 10.2 ml of bromoacetyl bromide and the mixture washeated to reflux temperature for 20 h. After cooling the crystals arefiltered off and these are then stirred for 30 min. in a mixture of 3 lof saturated aqueous sodium hydrogen (sic) carbonate solution and 1 l ofdichloromethane. The aqueous phase was separated and extracted againwith dichloromethane. The dichloromethane solutions were dried oversodium sulphate and evaporated. The dark brown crystalline residue (25g) was chromatographed over 400 g of silica gel. With toluene/ethylacetate 8:1 there were eluted 19.1 g of the desired product which wasrecrystallized from ethanol/diethyl ether. There were obtained 17.6 g of2-[2-(bromoacetylamino)-5-iodobenzoyl]-pyridine, which was used withoutfurther purification for the next step.

b) A solution of 5.4 g of hexamethylenetetramine in 400 ml of anhydrousethanol was saturated, with gaseous ammonia. The solution was heated to80° C. and 17.2 g of 2-[2-(bromoacetylamino)-5-iodobenzoyl]-pyridinewere added portionwise. The latter passed slowly into solution; crystalsseparated after 30 min. at 80° C. The mixture was stirred at refluxtemperature for 4 h. while introducing further ammonia. After coolingthe crystals were filtered off. 11.2 g of yellow crystals were obtained.After evaporation of the filtrate the residue was taken up in water. Thecrystals were filtered off (1.3 g). Both crystallizates wererecrystallized from ethanol. There were obtained 9.7 g of7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2(1H)-one, m.p. 251-252° C.(dec.).

c) A solution of 3.45 g of7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2(1H)-one in 80 ml ofhexamethylphosphoric acid triamide (HMPT) was treated with 4.24 g ofLawesson reagent and the mixture was stirred at 105° C. for 3.5 h. Thereaction mixture was poured into 600 ml of saturated aqueous sodiumhydrogen carbonate solution and 2 l of water. After stirring at roomtemperature for 30 min. the precipitate was filtered off. There wereobtained 3.0 g of crude, yellow7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione, m.p. 242° C.,which was used in this form for the next step.

d) 60 ml of 25% aqueous ammonia solution and 30 ml of methanol wereadded to a suspension of 3.0 g of7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione in 200 ml oftetrahydrofuran. The mixture was stirred at room temperature for 16 h.,with the solution which formed being concentrated to about 50 ml in avacuum. The crystals were filtered off, washed with water, dried,stirred in 25 ml of dioxan at 100° C., cooled and filtered off. Therewere obtained 2.35 g of2-amino-7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepine of m.p. 228-229° C.

e) A, solution of 2.3 g of2-amino-7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepine and 0.87 g of1,3-dichloroacetone in 65 ml of dioxan was treated with 0.6 g ofanhydrous sodium hydrogen carbonate and the mixture was stirred at 100°C. for 24 h. A further 0.09 g of dichloroacetone and 0.06 g of anhydroussodium hydrogen carbonate were added and the mixture was stirred at 100°C. for a further 5 h. The mixture was evaporated in a vacuum and theresidue was partitioned between chloroform and saturated aqueous sodiumhydrogen carbonate solution. The aqueous phase was extracted three timeswith chloroform. The chloroform extracts were dried over sodium sulphateand chromatographed over 200 g of silica gel. Withdichloromethane/ethanol 197:3 there were eluted small amounts ofimpurities, with dichloromethane/ethanol 195:5 there were eluted 1.3 gof the desired product. After recrystallization from ethyl acetate therewere obtained 1.21 g of 2-chloromethyl-8-iodo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine of m.p. 216° C. (dec.).

f) A solution of 1.15 g of2-chloromethyl-8-iodo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepinein 40 ml of dioxan was treated with a solution of 0.28 g of sodiumhydrogen carbonate in 10 ml of water and stirred at 80° C. for 1.5 h.The mixture was evaporated in a vacuum. The residue was partitionedbetween chloroform and aqueous sodium hydrogen carbonate solution. Theaqueous phase was extracted three times with chloroform. The chloroformextracts were dried over sodium sulphate, concentrated to 30 ml in avacuum and chromatographed over 50 g of silica gel. 1.05 g of thedesired product were eluted with chloroform/ethanol mixtures containing3 to 7% ethanol. After recrystallization from ethyl acetate/diethylether there was obtained 0.955 g of8-iodo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol ofm.p. 206-207° C. which was converted into the hydrochloride (dec. above300° C.).

EXAMPLE 21 Manufacture of2-acetoxymethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo-[1,2-a][1,4]benzodiazepine

0.96 ml of acetic anhydride was added dropwise to a solution of 1.36 gof8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolin 30 ml of pyridine. The reaction mixture was stirred at roomtemperature for 70 h. and then evaporated in a vacuum. The residue wastreated with saturated aqueous sodium hydrogen carbonate solution andthis was extracted twice with dichloromethane. The dichloromethaneextracts were dried over sodium sulphate and the solution waschromatographed over 50 g of silica gel. 1.4 g of an oil were elutedwith dichloromethane/ethanol 197:3 and this was crystallized fromdiethyl ether/diisopropyl ether. There were obtained 2.1 g of2-acetoxymethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine of m.p. 134-136° C. which was converted intothe hydrochloride.

What is claimed is:
 1. A hydroxymethyl-imidazodiazepine compound of theformula

wherein A and the two carbon atoms denoted by α and β together are oneof the residues

R¹ is hydrogen or lower-alkanoyl; R² is phenyl, o-halophenyl or2-pyridyl; R³ is hydrogen, lower-alkyl, methylaminomethyl,allylaminomethyl or diethylaminomethyl; R⁵ is hydrogen or halogen, orpharmaceutical acceptable salts or esters thereof.
 2. A compoundaccording to claim 1, wherein A is residue A².
 3. A compound accordingto claim 2, wherein R¹ is hydrogen or carbonylmethyl.
 4. A compoundaccording to claim 2, wherein R² is o-fluorophenyl.
 5. A compoundaccording to claim 2, wherein R³ is hydrogen.
 6. A compound according toclaim 2, wherein R⁵ is chlorine.
 7. A compound according to claim 1,wherein A is residue A², R¹ is hydrogen or carbonylmethyl, R² iso-fluorophenyl, R³ is hydrogen, and R⁵ is chlorine.
 8. A compoundaccording to claim 7, wherein the compound is2-chloro-4-(2-fluorophenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepine-8-methanol.9. A compound according to claim 7, wherein the compound ismethyl-[2-chloro-4-(2-fluorophenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f]diazepin-8-yl]acetate.10. A pharmaceutical composition comprising an effective amount of ahydroxymethyl-imidazodiazepine compound of the formula

wherein A and the two carbon atoms denoted by α and β together are oneof the residues

R¹ is hydrogen or lower-alkanoyl; R² is phenyl, o-halophenyl or2-pyridyl; R³ is hydrogen, lower-alkyl, methylaminomethyl,allylaminomethyl or diethylaminomethyl; R⁵ is hydrogen or halogen, orpharmaceutical acceptable salts and esters thereof; or apharmaceutically inert carrier.
 11. A pharmaceutical compositionaccording to claim 10, wherein A is residue A².
 12. A pharmaceuticalcomposition according to claim 11, wherein R¹ is hydrogen orcarbonylmethyl.
 13. A pharmaceutical composition according to claim 11,wherein R² is o-fluorophenyl.
 14. A pharmaceutical composition accordingto claim 11, wherein R³ is hydrogen.
 15. A pharmaceutical compositionaccording to claim 11, wherein R⁵ is chlorine.
 16. A pharmaceuticalcomposition according to claim 10, wherein A is residue A², R¹ ishydrogen or carbonylmethyl, R² is o-fluorophenyl, R³ is hydrogen, and R⁵is chlorine.
 17. A pharmaceutical composition according to claim 16,wherein the compound is2-chloro-4-(2-fluorophenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepine-8-methanol.18. A pharmaceutical composition according to claim 16, wherein thecompound ismethyl-[2-chloro-4-(2-fluorophenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f]diazepin-8-yl]acetate.